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TitleVaccine elicitation and structural basis for antibody protection against alphaviruses.
Journal, issue, pagesCell, Vol. 186, Issue 12, Page 2672-2689.e25, Year 2023
Publish dateJun 8, 2023
AuthorsMatthew S Sutton / Sergei Pletnev / Victoria Callahan / Sungyoul Ko / Yaroslav Tsybovsky / Tatsiana Bylund / Ryan G Casner / Gabriele Cerutti / Christina L Gardner / Veronica Guirguis / Raffaello Verardi / Baoshan Zhang / David Ambrozak / Margaret Beddall / Hong Lei / Eun Sung Yang / Tracy Liu / Amy R Henry / Reda Rawi / Arne Schön / Chaim A Schramm / Chen-Hsiang Shen / Wei Shi / Tyler Stephens / Yongping Yang / Maria Burgos Florez / Julie E Ledgerwood / Crystal W Burke / Lawrence Shapiro / Julie M Fox / Peter D Kwong / Mario Roederer /
PubMed AbstractAlphaviruses are RNA viruses that represent emerging public health threats. To identify protective antibodies, we immunized macaques with a mixture of western, eastern, and Venezuelan equine ...Alphaviruses are RNA viruses that represent emerging public health threats. To identify protective antibodies, we immunized macaques with a mixture of western, eastern, and Venezuelan equine encephalitis virus-like particles (VLPs), a regimen that protects against aerosol challenge with all three viruses. Single- and triple-virus-specific antibodies were isolated, and we identified 21 unique binding groups. Cryo-EM structures revealed that broad VLP binding inversely correlated with sequence and conformational variability. One triple-specific antibody, SKT05, bound proximal to the fusion peptide and neutralized all three Env-pseudotyped encephalitic alphaviruses by using different symmetry elements for recognition across VLPs. Neutralization in other assays (e.g., chimeric Sindbis virus) yielded variable results. SKT05 bound backbone atoms of sequence-diverse residues, enabling broad recognition despite sequence variability; accordingly, SKT05 protected mice against Venezuelan equine encephalitis virus, chikungunya virus, and Ross River virus challenges. Thus, a single vaccine-elicited antibody can protect in vivo against a broad range of alphaviruses.
External linksCell / PubMed:37295404 / PubMed Central
MethodsEM (single particle)
Resolution3.3 - 7.0 Å
Structure data

27389

8dec

EMDB-27389, PDB-8dec:
Cryo-EM Structure of Western Equine Encephalitis Virus
Method: EM (single particle) / Resolution: 4.7 Å

27390

8ded

EMDB-27390, PDB-8ded:
Cryo-EM Structure of Western Equine Encephalitis Virus VLP in complex with SKW19 fab
Method: EM (single particle) / Resolution: 4.1 Å

27391

8dee

EMDB-27391, PDB-8dee:
Asymmetric Unit of Western Equine Encephalitis Virus
Method: EM (single particle) / Resolution: 3.4 Å

27392

8def

EMDB-27392, PDB-8def:
Cryo-EM Structure of Western Equine Encephalitis Virus VLP in complex with SKW24 fab
Method: EM (single particle) / Resolution: 4.2 Å

27395

8deq

EMDB-27395, PDB-8deq:
Cryo-EM local refinement of antibody SKV09 in complex with VEEV alphavirus spike glycoprotein
Method: EM (single particle) / Resolution: 6.0 Å

27396

8der

EMDB-27396, PDB-8der:
Cryo-EM local refinement of antibody SKV16 in complex with VEEV alphavirus spike glycoprotein
Method: EM (single particle) / Resolution: 3.3 Å

27722

8dul

EMDB-27722, PDB-8dul:
Cryo-EM Structure of Antibody SKT05 in complex with Western Equine Encephalitis Virus spike (local refinement from VLP particles)
Method: EM (single particle) / Resolution: 4.17 Å

27723

8dun

EMDB-27723, PDB-8dun:
Cryo-EM Structure of Antibody SKW11 in complex with Western Equine Encephalitis Virus spike (local refinement from VLP particles)
Method: EM (single particle) / Resolution: 5.84 Å

27757

8dwo

EMDB-27757, PDB-8dwo:
Cryo-EM Structure of Eastern Equine Encephalitis Virus in complex with SKE26 Fab
Method: EM (single particle) / Resolution: 3.5 Å

EMDB-28056: Venezuelan equine encephalitis virus-like particle in complex with Fab SKT05
Method: EM (single particle) / Resolution: 4.1 Å

28058

8eeu

EMDB-28058: Venezuelan equine encephalitis virus-like particle in complex with Fab SKT05, local refinement
PDB-8eeu: Venezuelan equine encephalitis virus-like particle in complex with Fab SKT05
Method: EM (single particle) / Resolution: 3.5 Å

EMDB-28059: Venezuelan equine encephalitis virus-like particle in complex with Fab SKT20
Method: EM (single particle) / Resolution: 4.7 Å

28060

8eev

EMDB-28060: Venezuelan equine encephalitis virus-like particle in complex with Fab SKT-20, local refinement
PDB-8eev: Venezuelan equine encephalitis virus-like particle in complex with Fab SKT-20
Method: EM (single particle) / Resolution: 3.6 Å

EMDB-28115: Western Equine Encephalitis Virus-Like Particle in Complex with SKW19 Fab
Method: EM (single particle) / Resolution: 6.3 Å

EMDB-28116: Western Equine Encephalitis Virus-Like Particle in Complex with SKW24 Fab
Method: EM (single particle) / Resolution: 6.5 Å

EMDB-28117: Eastern Equine Encephalitis Virus-Like Particle in Complex with SKE26 Fab
Method: EM (single particle) / Resolution: 3.7 Å

EMDB-28118: Cryo-EM structure of Antibody SKW11 in complex with Western Equine Encephalitis Virus-Like Particle
Method: EM (single particle) / Resolution: 6.1 Å

EMDB-28119: Cryo-EM structure of Antibody SKT05 in complex with Western Equine Encephalitis Virus-like Particle
Method: EM (single particle) / Resolution: 5.7 Å

EMDB-28187: Cryo-EM I1 reconstruction of antibody SKV09 in complex with VEEV alphavirus VLP
Method: EM (single particle) / Resolution: 7.0 Å

EMDB-28188: Cryo-EM I1 reconstruction of antibody SKV16 in complex with VEEV alphavirus VLP
Method: EM (single particle) / Resolution: 5.8 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

Source
  • western equine encephalitis virus
  • homo sapiens (human)
  • venezuelan equine encephalitis virus
  • macaca (macaques)
  • macaca fascicularis (crab-eating macaque)
  • eastern equine encephalitis virus
KeywordsVIRUS LIKE PARTICLE / Western Equine Encephalitis Virus / Virus-Like Particle / VIRUS/IMMUNE SYSTEM / antibody / VLP-Fab complex / VIRUS-IMMUNE SYSTEM complex / VIRAL PROTEIN / antibody alphavirus VEEV spike trimer glycoprotein / IMMUNE SYSTEM / SKT05 / broadly neutralizing / SKW11 / Eastern Equine Encephalitis virus / virus-fab complex / VIRUS LIKE PARTICLE/IMMUNE SYSTEM / Venezuelan equine encephalitis virus / neutralizing antibody / VEEV / VIRUS LIKE PARTICLE-IMMUNE SYSTEM complex

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